Polymers with bio-functional self assembling monolayer endgroups for therapeutic applications and blood filtration

Abstract

Medical device, prosthesis, or packaging assembly made up of polymer body comprising at least one polymer having the formula R(LE)x wherein R is a polymeric core having a number average molecular weight of from 5000 to 7,000,000 daltons, and having x endgroups, x is an integer≧1, E is an endgroup which is covalently linked to polymeric core R by linkage L, L is a divalent oligomeric chain which has at least 5 repeat units and which can self-assembly with L chains on adjacent molecules of the polymer, and moieties L and/or E in the polymer(s) may be the same as or different from one another in composition and/or molecular weight. The polymer body includes plural polymer molecules located internally within the body, at least some of which internal polymer molecules have endgroups that form a surface of the body. The surface endgroups include at least one self-assembling moiety.

1 . An in vitro, ex vivo, or in vivo medical device or prosthesis or packaging assembly comprising a polymer body comprising at least one polymer having the formula
   R(LE) x      wherein   R is a polymeric core having a number average molecular weight of from 5,000 to 7,000,000 daltons, and having x endgroups,   x is an integer≧1,   E is an endgroup covalently linked to polymeric core R by linkage L,   L is a divalent oligomeric chain having at least 5 repeat units and is capable of self-assembly with L chains on adjacent molecules of the polymer, and the moieties L and/or E in the polymer(s) may be the same as or different from one another in composition and/or molecular weight, wherein the polymer body comprises a plurality of polymer molecules located internally within said body, at least some of which internal polymer molecules have endgroups that comprise a surface of the body, wherein the surface endgroups include at least one self-assembling moiety.   
   
   
       2 . The medical device of  claim 1 , which is made from a heparinized filtration or affinity therapy/purification medium constructed of a polymer of the formula Heparin-CH 2 —NH-SPACER-POLYMER-SPACER-NH—CH 2 -Heparin, wherein POLYMER is a polymeric core with a MW of ≧5,000 daltons and obtained by free radical addition polymerization, or by ionic polymerization, or by step growth condensation polymerization, wherein SPACER is a chemical moiety that is capable of self assembly by means of van der Waals interactions, or by electrostatic interactions, or by hydrogen bonding, or by ionic forces. 
   
   
       3 . The medical device of  claim 2 , wherein said polymer has a formula selected from the group consisting of:
 (a) Heparin-CH 1 —NH—(CH 2 ) n -polycarbonateurethane-(CH 2 ) n —NH—CH 2 -Heparin, wherein the polycarbonateurethane has a MW≧5,000 daltons, and wherein n is an integer greater than 4;   (h) Heparin-CH 2 —NH—(CH 2 ) n -polyetherurethane-(CH 2 ) n —NH—CH 2 -Heparin, wherein the polyetherurethane has a MW of ≧5.000 daltons, and wherein n is an integer greater than 4;   (c) Heparin-CH 2 —NH—(CH 2 ) n -polyetherpolyester-(CH 2 ) n —NH—CH 2 -Heparin, wherein the polyether-polyester has a MW of ≧5,000 daltons, and wherein n is an integer greater than 4;   (d) heparin-CH 2 —NH—(CH 2 ) n -polyetherpolyamide-(CH 2 ) n —NH—CH 2 -Heparin, wherein the polyether-polyamide has a MW of ≧5,000 daltons, and wherein n is an integer greater than 4;   (e) Heparin-CH 2 —NH—(CH 2 ) n -polycarbonatesiliconeurethane-(CH 2 ) n —NH—CH 2 -Heparin, wherein the polycarbonate-silicone-urethane has a MW of ≧5,000 daltons, and wherein n is an integer greater than 4;   (f) Heparin-CH 2 —NH—(CH 2 ) n -polyethersiliconeurethane-(CH 2 —NH—CH 2 -Heparin, wherein the polyether-silicone-urethane has a weight average MW of ≧5,000 daltons, and wherein n is an integer greater than 4;   (g) Heparin-CH 2 —NH—(CH 2 ) n -polyestersiliconeurethane-(CH 2 )—NH—CH 2 -Heparin, wherein the polyester-silicone-urethane has a MW of ≧5,000 daltons, and wherein n is an integer greater than 4;   (h) Heparin-CH 2 —NH—(CH 2 ) m —NH—(CH 2 ) n -polyolefin-(CH 2 ) n —NH—(CH 2 ) m —NH—CH 2 -Heparin, wherein the polyolefin is a homopolymer or a copolymer with or without functionalization or a polyolefin with different architectures, and having a weight average molecular weight of ≧5,000 daltons, and wherein m is ≧2, and wherein, n is ≧2;   (i) Heparin-CH 2 —NH—(CH 2 ) m —NH—(CH 2 ) n -polyolefin-(CH 2 ) n —NH—(CH 2 ) m —NH—CH 2 -Heparin, wherein the polyolefin core is a linear low density polyethylene having a weight average molecular weight of ≧5,000 daltons, and wherein m is ≧2, and wherein, n is ≧2;   (j) Heparin-CH 2 —NH—(CH 2 ) n -polyolefin-(CH 2 ) n —NH—CH 2 -Heparin, wherein the polyolefin is a homopolymer or a copolymer with or without functionalization and having a weight average molecular weight of ≧5 000 daltons, and wherein m is ≧2, and wherein, n is ≧2;   (k) Heparin-CH 2 —NH—(CH 2 ) n -polyolefin-(CH 2 ) n —NH—CH 2 -Heparin, wherein the polyolefin core is a linear low density polyethylene having a weight average molecular weight of ≧5,000 daltons, and wherein n is ≧2;   (l) R 1 —N(CH 3 ) 2   30 —(CH 2 ) 2 —OP(O) 2 O − —(CH 2 ) n -polyethylene-(CH 2 ) n —OP(O) 2 O 2 —(CH 2 ) 2 —N(CH 3 ) 2 —R 1   + , wherein the polyethylene core is a linear low density polyethylene having a weight average molecular weight of from ≧5,000 daltons, wherein n is ≧2, and wherein R 1  is a aliphatic alkyl group with number of carbon atoms between 1 to 21, or substituted and unsubstituted aromatic groups with number of carbon atoms up to 21;   (m) X − N + (CH 3 ) 2 (R 1 )—(CH 2 CH 2 O) n —C(O)NH-polyurethanecopolymer-NHC(O)—(OCH 2 CH 2 ) n —N + (CH 3 ) 2 (R 1 )X − , wherein polyurethanecopolymer is an aromatic polycarbonate-polyurethane block copolymer, or a polyetherurethane block copolymer, or a polyester-polyurethane block copolymer, or a polyurethane-polyurea block copolymer, or a polyurethane-urea polymer, having a weight average molecular weight of ≧5,000 daltons, and wherein n≧1, and wherein the counter ion X is halide or another counter-ions with charge localized on an oxygen atom, and wherein R 1  is an aliphatic alkyl group with between 6 and 22 carbons; and   (n) X − N + (CH 3 ) 2 —(R 1 )—(CH 2 CH 2 ) n —O—C(O)NH--polyurethanecopolymer-NHC(O)—O (CH 2 CH 2 ) n —N + (CH 3 ) 2 (R 1 )X − , wherein polyurethanecopolymer is an aliphatic polycarbonate-polyurethane block copolymer, or a polyether-polyurethane block copolymer, or a polyester-polyurethane block copolymer, or a polyurethane-polyurea block copolymer, or a polyurethaneurea polymer, having a weight average molecular weight of ≧5,000 daltons, and wherein n=≧1, and wherein the counter ion X is halide or another counter-ions with charge localized on an oxygen atom, and wherein R 1  is an aliphatic alkyl group with between 6 and 22 carbon atoms.   
   
   
       4 .- 16 . (canceled) 
   
   
       17 . The medical device of  claim 2 , wherein said SPACER is a self assembling moiety pendant to the POLYMER backbone. 
   
   
       18 . The medical device of  claim 2 , wherein said SPACER is a self assembling moiety located at the chain ends of the POLYMER. 
   
   
       19 . The medical device of  claim 2 , wherein said POLYMER is obtained by step growth condensation polymerization. 
   
   
       20 . The medical device or prosthesis or packaging assembly of  claim 1 , wherein said internal polymer molecules comprising at least one self-assembling molecular moiety which comprises a major portion of said polymer body and has a weight average molecular weight in the range 5 1 000-5,000,000 daltons. 
   
   
       21 . The medical device or prosthesis or packaging assembly of  claim 20 , wherein said internal polymer molecule has a weight average molecular weight in the range 50,000-5,000,000 daltons. 
   
   
       22 . The device or prosthesis of  claim 1 , configured as an implantable medical device or prosthesis or as a non-implantable disposable or extracorporeal medical device or prosthesis or as an in vitro or ex vivo or in vivo diagnostic device, wherein said device or prostheses has a tissue, fluid, and/or blood-contacting surface. 
   
   
       23 . The device or prosthesis of  claim 1 , wherein said polymer body comprises a dense or microporous membrane component in an implantable medical device or prosthesis or in a non-implantable disposable or extracorporeal medical device or prosthesis or as an in vitro or ex vivo or in vivo diagnostic device, and wherein, when said polymer body comprises a membrane component in a diagnostic device, said component contains immuno-reactants. 
   
   
       24 . The device or prosthesis of  claim 1 , wherein said device or prosthesis comprises a blood gas sensor, a compositional sensor, a substrate for combinatorial chemistry, a customizable active biochip, a semiconductor-based device for identifying and determining the function of genes, genetic mutations, and proteins, a drug discovery device, an immunochemical detection device, a glucose sensor, a pH sensor, a blood pressure sensor, a vascular catheter, a cardiac assist device, a prosthetic heart valve, an artificial heart, a vascular stent, a prosthetic spinal disc, a prosthetic spinal nucleus, a spine fixation device, a prosthetic joint, a cartilage repair device, a prosthetic tendon, a prosthetic ligament, a drug delivery device from which drug molecules are released over time, a drug delivery coating in which drugs are fixed permanently to polymer endgroups, a catheter balloon, a glove, a wound dressing, a blood collection device, a blood storage container, a blood processing device, a plasma filter or affinity therapy/purification cartridge, connectors, sampling ports, cannulae, tubing, a plasma filtration catheter, a device for bone or tissue fixation, a urinary stent, a urinary catheter, a contact lens, an intraocular lens, eye care product, an ophthalmic drug delivery device, a male condom, a female condom, devices and collection equipment for treating human infertility, a pacemaker lead, an implantable defibrillator lead, a neural stimulation lead, a scaffold for cell growth or tissue engineering, a prosthetic or cosmetic breast implant, a prosthetic or cosmetic pectoral implant, a prosthetic or cosmetic gluteus implant, a penile implant, an incontinence device, a laparoscope, a vessel or organ occlusion device, a bone plug, a hybrid artificial organ containing transplanted tissue, an in vitro or ex vivo or in vivo cell culture device, a blood filter, blood tubing, roller pump tubing, a cardiotomy reservoir, an oxygenator membrane, a dialysis membrane, an artificial lung, an artificial liver, or a column packing adsorbent or chelation agent for purifying or separating blood, plasma, or other fluids. 
   
   
       25 . The device or prosthesis of  claim 24 , wherein said device is a drug delivery device wherein the drug is complexed to surface-modifying endgroups and is released through diffusion or wherein the drug is associated with, complexed to, or covalently bound to surface-modifying endgroups that degrade and release the drug over time. 
   
   
       26 . The device or prosthesis of  claim 24 , wherein said device is microtubing for blood filtration, said tubing being composed of a heparinized copolymer of acrylonitrile and sodium methallyl sulfonate or of a heparinized polyurethane, wherein said tubing has an inside diameter of from 180 to 300 microns and an outside diameter of from 280 to 400 microns, provided that the difference between the inside diameter and the outside diameter ranges from 80 to 120 microns. 
   
   
       27 . The device or prosthesis of  claim 1 , configured as an implantable medical device or prosthesis or as a non-implantable disposable or extracorporeal medical device or prosthesis or as an in vitro or ex vivo or in vivo diagnostic device, wherein said device or prosthesis has antimicrobial activity afforded by self-assembling antimicrobial agents covalently bonded to the polymer chain as an endgroup. 
   
   
       28 . A packaging assembly in accordance with  claim 1 , wherein the polymer body comprises a plurality of polymer molecules located internally within said body, at least some of which internal polymer molecules have endgroups that comprise a surface of the body, wherein the surface endgroups include at least one self-assembling monolayer moiety,
 wherein the polymer comprising the self-assembling monolayer moieties in the polymer body is a first polymer making up the entirety of a major portion of the body and having a weight average molecular weight in the range 5,000-5,000,000 daltons, or is a second polymer, having a weight average molecular weight in the range 1,000-500,000 daltons, which comprises an additive to the first polymer making up the entirety or a major portion of the body, or   wherein said packaging assembly comprises a plastic bottle and eyedropper assembly containing a sterile solution, wherein said self-assembling monolayer moieties bind an antimicrobial agent and wherein said bound antimicrobial agents maintain the sterility of said solution.   
   
   
       29 . A method of immobilizing biologically-active entities, including proteins, peptides, and polysaccharides, at a surface of a polymer body, which polymer body surface comprises a surface of an interface, which method comprises the sequential steps of
 contacting the polymer body surface with a medium that delivers self-assembling monolayer moieties containing chemically-reactive groups, capable of binding biologically-active entities to the surface, to the polymer body surface by interaction of chemical groups, chains, or oligomers, said self-assembling monolayer moieties being covalently or ionically bonded to a polymer in the body and comprising one or more chemical groups, chains, or oligomers that spontaneously assemble in the outermost monolayer of the surface of the polymer body or one or more chemical groups, chains, or oligomers that spontaneously assemble within that portion of the polymer body that is at least one monolayer away form the outermost monolayer of the polymer body surface, and   binding said biologically-active entities to said reactive groups,   wherein the polymer comprising the self-assembling monolayer moieties in the polymer body is a first polymer making up the entirety of a major portion of the body and having a weight average molecular weight in the range 5,000-5,000,000 daltons, or is a second polymer, having a weight average molecular weight in the range 1,000-500,000 daltons, which comprises an additive to the first polymer making up the entirety or a major portion of the body, or   wherein said self-assembling monolayer moieties containing binding groups comprise methoxy ether-terminated polyethyleneoxide oligomers having one or more amino, hydroxyl, carboxaldehyde, or carboxyl groups along the polyethyleneoxide chain.   
   
   
       30 . The method of immobilizing biologically-active entities according to  claim 29 , wherein the polymer comprising the self-assembling monolayer moieties in the polymer body is a first polymer making up the entirety of a major portion of the body and having a weight average molecular weight in the range 5,000-5,000,000 daltons, or is a second polymer, having a weight average molecular weight in the range 1,000-500,000 daltons, which comprises an additive to the first polymer making up the entirety or a major portion of the body. 
   
   
       31 . The method of immobilizing biologically-active entities of  claim 29 , wherein said first polymer has a weight average molecular weight in the range 50,000-5,000,000 daltons. 
   
   
       32 . The medical device a prosthesis or packaging assembly of  claim 20 , wherein said polymer body further comprises a second polymer, having a weight average molecular weight in the range of 1,000-500,000 daltons, as an additive to said internal polymer molecules.